Dibenzo[d,g][1,3,6]dioxazocine derivatives

ABSTRACT

This invention relates to novel dibenzo[d,g][1,3,6]dioxazocine derivatives represented by the general formula I ##STR1## wherein R 1  and R 2  independently represent hydrogen, halogen, cyano or trifluoromethyl, 
     Y stands for hydrogen or a group of formula ##STR2##  wherein A stands for a straight or branched chained alkylene having from 2 to 5 carbon atoms and 
     R 3  and R 4  independently stand for an alkyl having from 1 to 4 carbon atoms, or 
     R 3  and R 4  together with the nitrogen atom they are attached to and optionally together with a further nitrogen atom or with an additional oxygen atom may form a five- or six-membered heterocyclic ring optionally substituted with an alkyl having from 1 to 4 carbon atoms, 
     and pharmaceutically acceptable acid addition salts thereof formed with an inorganic or organic acid. 
     The above compounds possess valuable pharmaceutical properties, for instance they are effective local anaesthetics and can be used for treating Parkinson syndrome.

This invention relates to new dibenzo[d,g][1,3,6]dioxazocine derivativesand to pharmaceutically acceptable, inorganic or organic acid additionsalts thereof. The new dibenzo[d,g][1,3,6]dioxazocine derivatives areencompassed by the general formula I ##STR3## wherein R₁ and R₂independently represent hydrogen, halogen, cyano or trifluoromethyl,

Y stands for hydrogen or a group of formula ##STR4## wherein A standsfor a straight or branched chained alkylene having from 2 to 5 carbonatoms and

R₃ and R₄ independently stand for an alkyl having from 1 to 4 carbonatoms, or

R₃ and R₄ together with the nitrogen atom they are attached to andoptionally together with a further nitrogen atom or with an additionaloxygen atom may form a five- or six-membered heterocyclic ringoptionally substituted with an alkyl having from 1 to 4 carbon atoms.

The compounds of the general formula I possess valuable biologicalactivities, for instance they are effective local anaesthetics and canbe used for treating Parkinson syndrome.

Also the dibenzo[d,g][1,3,6]dioxazocine structure of the new compoundshaving the general formula I is new. The structurally closest compounds,i.e. the 5,11-dihydrodibenzo[b,e][1,4]oxazepine and7,12-dihydro-6H-dibenz[b,e][1,4]oxazocine derivatives are described inthe U.S. Pat. No. 3,591,604. These known compounds show ataractic andantihistamine activity.

In the general formula I Y preferably stands for a group wherein Astands for an ethylene, propylene, or isobutylene group, and R₃ and R₄each represent a methyl group. More preferably, R₃ and R₄ together withthe nitrogen atom they are attached to form a pyrrolidine, piperidine orpyridine ring or together with a further nitrogen or with an additionaloxygen form a piperazine or morpholine ring.

The most preferred representatives of the pharmaceutically acceptableacid addition salts of the compounds according to the invention aresalts formed with hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, acetic acid, citric acid, oxalic acid, maleic acid,tartaric acid and succinic acid.

The compounds of the general formula I and their pharmaceuticallyacceptable acid addition salts can be prepared by

(a) for preparing a compound of the general formula III belonging to anarrower group of the compounds having the general formula I ##STR5##wherein R₁ and R₂ are as defined above, heating a compound of thegeneral formula II ##STR6## wherein R₁ and R₂ are as defined above,

X₁ stands for halogen and

Q is hydrogen or formyl,

at 140° to 280° C., preferably at 160° to 240° C., or

(b) for preparing a compound of the general formula III, belonging to anarrower group of the compounds having the general formula I, wherein R₁and R₂ are as defined above, reacting a compound of the general formulaIV ##STR7## wherein R₁, R₂ and Q are as defined above, with adihalomethane of the general formula V

    X.sub.2 --CH.sub.2 --X.sub.3                               (V)

wherein X₂ and X₃ independently represent halogen, and, if desired,aminoalkylating the compound obtained with an aminoalkyl halide of thegeneral formula VI ##STR8## wherein R₃ and R₄ are as defined above andX₄ is halogen, or alkylating the same with a compound of the generalformula VII

    X.sub.5 --A--X.sub.6                                       (VII)

wherein X₅ and X₆ stand for halogen, and aminating the haloalkylderivative obtained with a compound of the general formula VIII ##STR9##wherein R₃ and R₄ have the same meaning as above, and, if desired,converting a compound of the general formula I obtained into an organicor inorganic pharmaceutically acceptable acid addition salt, orconverting an acid addition salt into the free base of general formulaI.

In the starting compounds of the general formula II in process variant(a) X₁ preferably is bromine. The reaction is preferably performed inthe presence of a base and a catalyst. As a base for example sodiumcarbonate, potassium carbonate or butyl-lithium can be used, out ofwhich the use of potassium carbonate proved to be especiallyadvantageous. Suitable catalysts are for instance copper powder, cupricchloride or heavy metal salts.

The temperatures of from 140° to 280° C., preferably from 160° to 240°C., are advantageously achieved in a reaction-inert heat medium theboiling point of which is not lower than the reaction temperature used.For this purpose the eutectic mixture of diphenyl and diphenyl ether isespecially advantageous. The commercial name of this medium is Dowtherm®A.

The compounds of the general formula II can be prepared according to amethod set forth in the U.S. Pat. No. 3,591,604.

In the process variant (b) compounds having the general formula IV arereacted with compounds of the general formula V in the presence of apolar solvent and a base. As a polar solvent both protic and aproticsolvents can be used. The reaction is preferably carried out in thepresence of an aliphatic alcohol, e.g. ethanol or N,N-dimethylacetamide.As a base for example sodium metal, sodium hydride or potassiumcarbonate are generally used.

Compounds having the general formula IV, in which Q stands for hydrogen,can be prepared for example by following the procedure described inpublication referred to in Chemical Abstracts, 60, 8022e (1964). TheN-formylation of these compounds can be accomplished according to amethod described in Beilstein's Handbuch fur organische Chemie, Volume12, p. 235.

The aminoalkylation of a dibenzo[d,g][1,3,6]dioxazocine derivativehaving the general formula III with a compound having the generalformula VI is preferably effected in a polar or apolar solvent, such asxylene or methyl ethyl ketone, in the presence of a base, such as sodiumhydroxide or potassium hydroxide.

The aminoalkylation of the compounds having the general formula III canbe accomplished also in two reaction steps. In the first step a compoundof the general formula III is alkylated with an α,ω-dihaloalkane havingthe general formula VII, and in the second step the ω-haloalkyl compoundobtained is reacted with an amine of the general formula VIII.

The reaction conditions during the reaction of a compound having thegeneral formula III with an α,ω-dihaloalkane of the general formula VIIare identical with the reaction conditions described above foraminoalkylation. Amination can be accomplished in the presence orabsence of a solvent. Depending on the amine having the general formulaVIII the reaction can be carried out under elevated or atmosphericpressure. The reaction temperature preferably is from 80° to 140° C.

The compounds of the general formula I and the inorganic and organic,pharmaceutically acceptable acid addition salts thereof show a prolongedlocal anaesthetic and antiparkinsonic activity.

Acute toxicity of the compounds was tested on white mice from the strainCFLP. Administration was effected perorally. The LD₅₀ -values obtainedare set forth in the following Table I.

                  Table 1                                                         ______________________________________                                        Acute toxicity                                                                Example No.       LD.sub.50 (mg./kg.) p.o.                                    ______________________________________                                        1                 >2000                                                       3                 760                                                         5                 700                                                         6                 270                                                         7                 600                                                         8                 >2000                                                       15                320                                                         ______________________________________                                    

In order to observe the local anaesthetic activity of the instantcompounds 0.25% and 0.5% solution thereof were tested following themethod described in Acta Chirurg. Scand. 116, 351 (1958). The testanimals were mice.

The concentration at which the activity amounted to 50% (EC₅₀) wasdetermined for the test compounds and for Lidocaine(2-diethylamino-2',6'-acetoxy-xylidide) used for comparison. The resultsobtained are listed in Table II below. In order to make possible adirect comparison of the test compounds with Lidocaine also the LD₅₀/EC₅₀ -values are given in Table II.

                  Table II                                                        ______________________________________                                        Local anaesthetic activity                                                    Example No.    EC.sub.50 (%)                                                                              LD.sub.50 /EC.sub.50                              ______________________________________                                        3              0.15         5060                                              5              0.32         2180                                              6              0.12         2250                                              7              0.13         4600                                              Lidocaine      0.18         1120                                              ______________________________________                                    

From Table II it can clearly be seen that the LD₅₀ /EC₅₀ -value for thecompounds according to the invention is 2 to 4.5-times higher than thatof Lidocaine.

Since in addition to activity and toxicity also the duration of theactivity plays an important role concerning the local anaestheticactivity, the duration of the effect obtained with 0.25% and 0.5%solutions was also observed. The results obtained are listed in TableIII below.

                  Table III                                                       ______________________________________                                        Duration of the local anaesthetic effect                                                              Duration of the effect                                Example No.                                                                              Concentration                                                                              (min.)                                                ______________________________________                                        3          0.25         71                                                               0.5          103                                                   5          0.25         34                                                               0.5          65                                                    6          0.25         67                                                               0.5          161                                                   7          0.25         53                                                               0.5          260                                                   Lidocaine  0.25         25                                                               0.5          37                                                    ______________________________________                                    

From the data listed in the above Table III it can be seen that thecompounds according to the invention have a much more prolonged activitythan Lidocaine, using either of the two concentrations, i.e. they indeedpossess a prolonged local anaesthetic activity.

As it has already been stated compounds of the general formula I alsoexert an antiparkinsonic activity. This activity was tested on whitemice, on the basis of the inhibition of tremor induced by tremorine[1,1'-(2-butynylene)-dipyrrolidine] and of nicotine lethality. Theresults are set forth in the Tables IV and V below. For comparisonTrihexyphenidyl [α-cyclohexyl-α-phenyl-1-piperidinepropanolhydrochloride] and L-DOPA [L-(-)-β-(3,4-dihydroxyphenyl)alanine] areused.

                  Table IV                                                        ______________________________________                                        Inhibition of tremor by tremorinne                                            (test method: Science, 124, 79/1956/)                                         Example No.   ED.sub.50 (mg./kg.) p.o.                                                                     LD.sub.50 /ED.sub.50                             ______________________________________                                        3             8              95                                               5             18             38.9                                             6             11             25                                               7             30             20                                               15            4.3            74.4                                             Trihexyphenidyl                                                                             15             24                                               L-DOPA        >500           <5                                               ______________________________________                                    

                  Table V                                                         ______________________________________                                        Inhibition of nicotine lethality                                              (test method: Pharmacodyn., 117, 419/1958/)                                   Example No.   ED.sub.50 (mg./kg.) p.o.                                                                     LD.sub.50 /ED.sub.50                             ______________________________________                                        3             14             54                                               5             60             12                                               6             11             25                                               8             140            14                                               15            9              35.6                                             Trihexyphenidyl                                                                             80             4.5                                              L-DOPA        500            <10                                              ______________________________________                                    

From the data given in Tables IV and V it appears that theantiparkinsonic activity of the compounds according to the inventionsurpasses that of the known compounds used for comparison.

The compounds of the general formula I and pharmaceutically acceptableacid addition salts thereof can be converted into pharmaceuticalcompositions, in a manner known per se, by using conventional carriersand optionally other known additives. Thus, for oral administrationtablets, capsules, dragees etc.; injectable solutions, suspensions oremulsions; or aerosol formulations can be prepared. A typical dose foradult patients is 2 to 200 mg./kg.

Further details of the invention are illustrated by the followingnon-limiting Examples.

EXAMPLE 1 2-Chloro-12H-dibenzo[d,g][1,3,6]dioxazocine

A suspension of 1.4 g. (0.004 moles) of(2-bromophenoxy)-(2-formamido-4-chlorophenoxy)-methane (m.p.: 98° to100° C.), 0.6 g. (0.0042 moles) of potassium carbonate, 0.2 g. of copperpowder and 12 ml. of Dowtherm® is heated up to 180° C. and is vigorouslystirred at this temperature for 8 hours. The reaction mixture isfiltered while hot, then the solvent is evaporated in vacuo. Theremaining dark tar is hydrolyzed by boiling in a mixture of 20 ml. ofethanol and 2 ml. of a 20% aqueous sodium hydroxide solution for onehour. The reaction mixture is cooled and neutralized with a 37% aqueoushydrogen chloride solution. The solvent is evaporated and the brownsolid residue is extracted with 10 ml. of hot benzene. Thereafter thesolvent is eliminated and the residue is crystallized from benzine.

Recrystallization of the crude product from a mixture of 30 ml. ofcyclohexane and 2 ml. of xylene affords 0.45 g. (45.6%) of a whiteproduct, melting at 182° to 184° C.

Analysis for C₁₃ H₁₀ ClNO₂ (molecular weight: 247.688): Calculated: C,63.05%; H, 4.07%; Cl, 14.32%; N,5.66%; Found: C, 63.46%; H, 4.29%; Cl,14.33%; N,5.64%.

EXAMPLE 22-Chloro-12H-12-(3-dimethylaminopropyl)-dibenzo[d,g][1,3,6]dioxazocine

A suspension of 1.1 g. (0.0045 moles) of2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine and 1.1 g. (0.027 moles) ofdry, powdered sodium hydroxide in 20 ml. of xylene is refluxed for threehours in a flask equipped with a water separator, with stirring.Thereafter a solution of 1.62 g. (0.013 moles) of 3-dimethylaminopropylchloride in 15 ml. of xylene is added in 0.5 hours. The reaction mixtureis boiled for 12 hours, cooled to room temperature, then 30 ml. of waterare added and the aqueous and organic phases are separated. To thexylene phase a solution of 3.3 g. (0.022 moles) of tartaric acid in 25ml. of water is added and the mixture is stirred for one hour. Theaqueous phase is separated and 30 ml. of benzine and 6.4 ml. (0.046moles) of a 25% aqueous ammonium hydroxide solution are added undervigorous stirring. After separation the benzine phase is dried onignited magnesium sulphate. The solvent is eliminated. Distillation ofthe crude product obtained in vacuo affords 1.21 g. (81.8%) of a whitecrystalline product, melting at 43° to 45° C. Boiling point/0.4 mmHg:185° to 190° C.

Analysis for C₁₈ H₂₁ ClN₂ O₂ (molecular weight: 332.833): Calculated: C,64.96%; H, 6.36%; Cl, 10.65%; N, 8.42%; Found: C, 65.78%; H, 6.66%; Cl,10.52%; N, 8.40%.

EXAMPLE 32-Chloro-12H-12-(3-dimethylaminopropyl)-dibenzo[d,g][1,3,6]dioxazocinemaleinate

To a solution of 1.56 g. (0.0047 moles) of2-chloro-12H-12-(3-dimethylaminopropyl)-dibenzo/d,g//1,3,6/dioxazocinein 20 ml. of abs. ether a solution of 0.7 g. (0.06 moles) of maleic acidin 40 ml. of abs. ether is added at 0° C. with stirring. Stirring iscontinued for one hour, whereupon the precipitated product is filteredoff and washed with abs. ether. Recrystallization from isopropanolaffords 1.51 g. (71.7%) of a snow-white product, melting at 132° to 135°C.

Analysis for C₂₂ H₂₅ ClN₂ O₆ (molecular weight: 448.915): Calculated: C,58.56%; H, 5.61%; Cl, 7.90%; N, 6.24%; Found: C, 59.26%; H, 5.65%; Cl,7.89%; N, 6.17%.

EXAMPLE 42-Chloro-12H-12-(2-piperidinoethyl)-dibenzo[d,g][1,3,6]dioxazocine

A suspension of 2.8 g. (0.0113 moles) of2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine and 3.1 g. (0.078 moles) ofdry powdered sodium hydroxide in 70 ml. of xylene is refluxed in a flaskequipped with a water separator for 3 hours, with stirring. Thereafter asolution of 5.0 g. (0.034 moles) of N-(2-chloroethyl)-piperidine in 30ml. of xylene is added in 0.5 hours and the reaction mixture is stirredfor further 12 hours.

Thereafter the reaction mixture is subjected to a treatment described inExample 2. Recrystallization of the product from isopropanol affords3.44 g. (85.6%) of a white product, melting at 87° to 89° C.

Analysis for C₂₀ H₂₃ ClN₂ O₂ (molecular weight: 358.877): Calculated: C,66.94%; H, 6.46%; Cl, 9.88%; N, 7.81; Found: C, 66.15%; H, 7.40%; Cl,9.98%; N, 7.90%.

EXAMPLE 52-Chloro-12H-12-(2-piperidinoethyl)-dibenzo[d,g][1,3,6]dioxazocinehydrochloride

A solution of 3.44 g. (0.0096 moles) of2-chloro-12H-12-(2-piperidinoethyl)-dibenzo[d,g][1,3,6]dioxazocine in 40ml. of abs. ether is cooled to 0° C. and the pH is adjusted to 2 to 3 byadding a suitable amount of a 15% solution of hydrochloric acid in etherwith stirring. The precipitated white crystals are filtered off,suspended in ether and washed.

Recrystallization of the product from isopropanol affords 3.17 g.(83.6%) of a snow-white product, melting at 201° to 203° C.

Analysis: for C₂₀ H₂₄ Cl₂ N₂ O₂ (molecular weight: 395.342): Calculated:C, 60.76%; H, 6.12%; Cl, 17.94%; N, 7.09%; Cl⁻,8.97%; Found: C, 59.94%;H, 5.69%; Cl, 17.97%; N, 7.17%; Cl⁻,8.95%.

EXAMPLE 62-Chloro-12H-12-(2-methyl-3-dimethylaminopropyl)dibenzo[d,g][1,3,6]dioxazocinehydrochloride

A suspension of 1.44 g. (0.058 moles) of2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine and 1.4 g. (0.036 moles) ofsolid, powdered sodium hydroxide in 30 ml. of xylene is refluxed in aflask equipped with a water separator for 3 hours. To the mixture asolution of 2.46 g. (0.0174 moles) of 2-methyl-3-dimethylaminopropylchloride in 15 ml. of xylene is added in 0.5 hours and the reactionmixture is boiled for further 12 hours.

The reaction mixture is thereafter subjected to the same treatment asdescribed in Example 2, which results in a white product weighing 1.83g. (90.6%) and melting at 72° to 75° C. The base is converted into thecorresponding hydrochloric acid addition salt according to the proceduredescribed in Example 5.

Recrystallization of the crude product from isopropanol affords 1.63 g.(73.2%) of a white product, melting at 184° to 186° C.

Analysis for C₁₉ H₂₄ Cl₂ N₂ O₂ (molecular weight: 383.331): Calculated:C, 59.53%; H, 6.31%; Cl, 18.50%; N, 7.31%; Cl⁻, 9.25%; Found: C, 59.66%;H, 6.38%; Cl, 18.57%; N, 7.35%; Cl⁻, 9.23%.

EXAMPLE 72-Chloro-12H-12-[2-(N-methylpiperazino)-ethyl]dibenzo[d,g][1,3,6]dioxazocinedihydrochloride

A suspension of 1.24 g. (0.005 moles) of2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine and 1.2 g. (0.03 moles) ofsolid, powdered sodium hydroxide in 20 ml. of xylene is refluxed in aflask equipped with a water separator for 3 hours, with stirring. Asolution of 2.44 g. (0.015 moles) of1-methyl-4-(2-chloroethyl)-piperazine in 20 ml. of xylene is addedwithin 0.5 hours and the mixture is boiled for further 12 hours.

The reaction mixture is thereafter subjected to the same treatment asdescribed in Example 2, which results in a crude base weighing 1.51 g.The crude product cannot be crystallized. The base is converted into thecorresponding hydrochloric acid addition salt according to the proceduredescribed in Example 5.

Recrystallization of the crude product from methanol affords 1.61 g.(72.2%) of a snow-white product, melting at 201° to 203° C.

Analysis for C₂₀ H₂₆ Cl₃ N₃ O₂ (molecular weight: 446.823): Calculated:C, 53.76%; H, 5.87%; Cl, 23.81%; N, 9.41%; Found: C, 52.55%; H, 5.80%;Cl, 23.52%; N, 9.35%.

EXAMPLE 82-Chloro-12H-12-(2-morpholinoethyl)-dibenzo[d,g][1,3,6]dioxazocinemaleinate

A suspension of 0.99 g. (0.004 moles) of2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine and 0.96 g. (0.024 moles) ofsolid, powdered sodium hydroxide in 20 ml. of xylene is refluxed in aflask equipped with a water separator for 3 hours, with stirring. To thereaction mixture a solution of 1.79 g. (0.012 moles) ofN-(2-chloroethyl)morpholine in 12 ml. of xylene is added in 0.5 hours,whereupon the mixture is boiled for further 12 hours.

Thereafter the reaction mixture is subjected to the same treatment asdescribed in Example 2, which results in a crude base weighing 1.0 g.

The base is converted into the corresponding maleinate salt in the wayset forth in Example 3. Recrystallization of the crude product fromisopropanol affords 1.04 g. (54.8%) of a snow-white product, melting at151° to 152° C.

Analysis for C₂₃ H₂₅ ClN₂ O₇ (molecular weight: 476.926): Calculated: C,57.92%; H, 5.28%; Cl, 7.43%; N, 5.88%; Found: C, 58.19%; H, 5.45%; Cl,7.49%; N, 5.87%.

EXAMPLE 92-Chloro-12H-12-(3-dimethylaminopropyl)-dibenzo[d,g][1,3,6]dioxazocine

A. A suspension of 2.48 g. (0.01 moles) of2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine, 6.3 g. (0.04 moles) of3-chlorobromopropane and 3.2 g. (0.08 moles) of sodium hydroxide in 30ml. of methyl ethyl ketone is refluxed for 8 hours, with vigorousstirring. A second 3.2 g. portion (0.08 moles) of sodium hydroxide isadded to the mixture, which is then refluxed for further 12 hours. Thereaction mixture is cooled to room temperature, poured on 30 ml. ofice-water and the organic and aqueous phases are separated from eachother. The aqueous phase is extracted with 10 ml. of methyl ethylketone. The organic phases are combined, washed with a saturated aqueoussodium chloride solution and dried over magnesium sulphate. Evaporationof the solvent gives a viscous residue, which turns to a crystallinesubstance spontaneously.

Recrystallization from isopropanol affords 2.0 g. (62.5%) of white2-chloro-12H-12-(3-chloropropyl)-dibenzo[d,g][1,3,6]dioxazocine, meltingat 106° to 108° C.

Analysis for C₁₆ H₁₅ Cl₂ NO₂ (molecular weight: 324.218): Calculated: C,59.27%; H, 4.66%; Cl, 21.87%; N, 4.32%; Found: C, 59.34%; H, 4.97%; Cl,21.79%; N, 4.25%.

B. A solution of 3.24 g. (0.01 moles) of2-chloro-12H-12-(3-chloropropyl)-dibenzo[d,g][1,3,6]dioxazocine and 4.5g. (0.10 moles) of dimethyl amine in 30 ml. of benzene is placed into abumb tube. The equipment is closed, heated up to 100° C. and kept atthis temperature for 20 hours. The reaction mixture is then cooled toroom temperature, washed three times with 10 ml. portions each of water,the organic phase is separated and the solvent is eliminated. Theresidue is dissolved in 30 ml. of ether and the solution is extractedwith two 20-ml. portions of a 2 N aqueous hydrochloric acid solution.The acid extracts are combined, washed with 10 ml. of ether, whereuponthe pH-value is adjusted to 10 with 20% aqueous sodium hydroxidesolution. The mixture is eluted with three 10-ml. portions of ether, thecombined ethereal extracts are washed with water and dried overmagnesium sulphate. The solvent is eliminated and the remaining crudebase is purified as described in Example 2 to give 1.34 g. (52.3%) of apure base. Melting point and analysis data of the product are identicalwith the corresponding characteristics of the compound obtained in StepA of this Example.

EXAMPLE 10 2,10-Dichloro-12H-dibenzo[d,g][1,3,6]dioxazocine

A suspension of 4.1 g. (0.01 moles) of(2-bromo-4-chlorophenoxy)-(2-formamido-4-chlorophenoxy)-methane (m.p.:148° to 149° C.), 2.1 g. (0.015 moles) of potassium carbonate, 0.5 g.(0.008 gatom) of copper powder and 30 ml. of Dowtherm® A is heated up to190° C. and is kept at this temperature for 10 hours, while stirredvigorously. Thereafter the reaction mixture is filtered and from thefiltrate the solvent is distilled off in vacuo. The remaining tar isboiled in a mixture of 45 ml. of ethanol and 4.5 ml. of a 20% aqueoussodium hydroxide solution for one hour, then cooled to 20° C. It is thenneutralized with a 37% aqueous hydrochloric acid solution and thesolvent is eliminated. The residue is extracted three times with 80 ml.portions each of hot cyclohexane, the combined extracts are decolouredwhile hot and the solvent is eliminated. Recrystallization of the crudeproduct from carbon tetrachloride affords a white product weighing 0.6g. (21.4%) and melting at 194° to 196° C.

Analysis for C₁₃ H₉ Cl₂ NO₂ (molecular weight: 282.137): Calculated: C,55.34%; H, 3.22%; Cl, 25.13%; N, 4.96%; Found: C, 55.68%; H, 3.47%; Cl,25.08%; N, 4.85%.

EXAMPLE 11 2,10-Dichloro-12H-dibenzo[d,g][1,3,6]dioxazocine

To a suspension of 1.17 g. (0.049 moles) of sodium hydride in 40 ml. ofN,N-dimethyl acetamide a solution of 6.07 g. (0.02 moles) of2,2'-dihydroxy-5,5'-dichloro-N-formyl-diphenylamine (m.p.: 180° to 182°C.) is added in one hour, at 25° C., under stirring. The mixture isstirred for a further one hour and 3.55 g. (0.02 moles) of methylenebromide are added to the clear solution in 0.5 hour. The reactionmixture is stirred at 25° C. for 5 hours and subsequently at a waterbath for 3 hours. 2/3 of the solvent are eliminated and the residue iscooled to room temperature and poured onto 100 g. of granulated ice. Theprecipitated solid is filtered off, washed and dried. Recrystallizationfrom carbon tetrachloride affords 3.51 g. (61%) of a white product,melting at 194° to 196° C. The product proved to be identical with theproduct of Example 10.

EXAMPLE 12 12H-dibenzo[d,g][1,3,6]dioxazocine

1.0 g. (0.044 gatoms) of sodium metal is dissolved in 50 ml. of ethanol.To the solution obtained a solution of 5.0 g. (0.0218 moles) of2,2'-dihydroxy-N-formyl-diphenylamine (m.p.: 152° to 155° C.) in 50 ml.of ethanol is added. To the clear solution 3.8 g. (0.021 moles) ofmethylene bromide are added at 25° C., under stirring. The reactionmixture is boiled for 5 hours, whereupon the solvent is eliminated. Theremaining tar is extracted with three 30 ml. portions of hot carbontetrachloride, filtered while hot and the filtrate is concentrated.

Recrystallization of the residue from ethanol affords 1.5 g. (20%) of awhite product, melting at 189° to 191° C.

Analysis for C₁₃ H₁₁ NO₂ (molecular weight: 213.24): Calculated: C,73.22%; H, 5.20%; N, 6.57%; Found: C, 73.36%; H, 5.41%; N, 6.44%.

EXAMPLE 13 2,10-Dichloro-12H-dibenzo[d,g][1,3,6]dioxazocine

A mixture of 6.3 g. (0.021 moles) of2,2'-dihydroxy-5,5'-dichloro-N-formyl-diphenylamine, 3.8 g. (0.022moles) of dibromomethane, 4.1 g. (0.03 moles) of anhydrous potassiumcarbonate and 100 ml. of N,N-dimethyl acetamide is heated up to 100° C.and is kept at this temperature for 12 hours under nitrogen, undervigorous stirring.

The reaction mixture is cooled to room temperature and poured on ice.The precipitated product is filtered off, washed with water andsubsequently dried. It is then hydrolyzed by boiling with a mixture of50 ml. of ethanol and 10 ml. of a 20% aqueous sodium hydroxide solutionfor one hour. Upon cooling the reaction mixture is neutralized with a37% aqueous hydrochloric acid solution, then the product is precipitatedby adding 100 ml. of water, filtered off, washed with water and dried.Repeated recrystallization from carbon tetrachloride affords 3.3 g.(55.6%) of a white product. Melting point and analysis data of theproduct are identical with those of the product of Example 11.

EXAMPLE 14 2-Chloro-12H-dibenzo[d,g][1,3,6]dioxazocine

A mixture of 6.7 g. (0.025 moles) of2,2'-dihydroxy-5-chloro-N-formyl-diphenylamine (m.p.: 154° to 157° C.),4.9 g. (0.03 moles) of dibromomethane, 17.5 g. (0.13 moles) of anhydrouspotassium carbonate and 120 ml. of N,N-dimethylacetamide is heated up to100° C. under nitrogen and kept at this temperature for 12 hours, undervigorous stirring.

The reaction mixture is cooled to room temperature, poured onto ice andthe precipitated solid is filtered off, washed with water and dried.Thereafter it is hydrolyzed by boiling in a mixture of 50 ml. of ethanoland 10 ml. of a 20% aqueous sodium hydroxide solution for one hour. Thereaction mixture is cooled down, neutralized with a 37% aqueoushydrochloric acid solution and the product is precipitated by addingwater to the mixture. The product is filtered off and dried.Recrystallization from isopropanol containing 20% by weight affords 4.3g. (68%) of a white product. Melting point and analysis data of theproduct obtained are identical with those of the product of Example 1.

EXAMPLE 152,10-Dichloro-12H-12-(3-dimethylaminopropyl)-dibenzo[d,g][1,3,6]dioxazocinemaleinate

A mixture of 11.3 g. (0.04 moles) of2,10-dichloro-12H-dibenzo[d,g][1,3,6]dioxazocine, 9.6 g. (0.24 moles) ofsodium hydroxide and 450 ml. of xylene is boiled in a flask equippedwith a water separator for two hours, with vigorous stirring. Thereaftera solution of 19.4 g. (0.16 moles) of 3-dimethylaminopropyl chloride in250 ml. of xylene is added to the reaction mixture, followed by theaddition of 2.0 g. of potassium iodide, and the mixture is boiled forfurther 12 hours. The reaction mixture is thereafter subjected to atreatment as described in Example 2 to give 14.0 g. of a crude basewhich cannot be crystallized.

To a solution of 14.0 g. (0.0382 moles) of a crude base in 150 ml. ofabs. ether 4.4 g. (0.0382 moles) of maleic acid in 320 ml. of abs. etherare added under stirring. The mixture is stirred for one hour andthereafter the precipitated product is washed with abs. ether.Recrystallization from acetonitrile affords 13.4 g. (69.5%) of asnow-white product, melting at 190° to 193° C. (decomposition).

Analysis for C₂₂ H₂₄ Cl₂ N₂ O₆ (molecular weight: 483.364): Calculated:C, 54.67%; H, 5.01%; Cl, 14.67%; N, 5.80%; Found: C, 54.82%; H, 4.96%;Cl, 14.54%; N, 5.70%.

What we claim is:
 1. Compounds of the general formula I ##STR10##wherein R₁ and R₂ independently represent hydrogen or halogen, andYstands for a group of formula ##STR11## wherein A stands for a straightor branched chained alkylene having from 2 to 5 carbon atoms andR₃ andR₄ independently stand for an alkyl having from 1 to 4 carbon atoms,andpharmaceutically acceptable acid addition salts thereof formed with aninorganic or organic acid.
 2. A compound as claimed in claim 1, which is2-chloro-12H-12-(3-dimethylaminopropyl)-dibenzo[d,g][1,3,6]dioxazocineand pharmaceutically acceptable acid addition salts thereof.
 3. Acompound as claimed in claim 1, which is2-chloro-12H-12-(2-methyl-3-dimethylaminopropyl)dibenzo[d,g][1,3,6]dioxazocineand pharmaceutically acceptable acid addition salts thereof.
 4. Acompound as claimed in claim 1, which is2,10-dichloro-12H-12-(3-dimethylaminopropyl)-dibenzo[d,g][1,3,6]dioxazocineand pharmaceutically acceptable acid addition salts thereof.
 5. Apharmaceutical composition effective as a local anesthetic and fortreating Parkinson syndrome, comprising a therapeutically effectiveamount of a compound as claimed in claim 1, in admixture with apharmaceutically acceptable excipient.